Osteopontin Negatively Regulates Parathyroid Hormone Receptor Signaling in Osteoblasts

Abstract

Systemic hormonal control exerts its effect through the regulation of local target tissues, which in turn regulate upstream signals in a feedback loop. The parathyroid hormone (PTH) axis is a well defined hormonal signaling system that regulates calcium levels and bone metabolism. To understand the interplay between systemic and local signaling in bone, we examined the effects of deficiency of the bone matrix protein osteopontin (OPN) on the systemic effects of PTH specifically within osteoblastic cell lineages. Parathyroid hormone receptor (PPR) transgenic mice expressing a constitutively active form of the receptor (caPPR) specifically in cells of the osteoblast lineage have a high bone mass phenotype. In these mice, OPN deficiency further increased bone mass. This increase was associated with conversion of the major intertrabecular cell population from hematopoietic cells to stromal/osteoblastic cells and parallel elevations in histomorphometric and biochemical parameters of bone formation and resorption. Treatment with small interfering RNA (siRNA) for osteopontin enhanced H223R mutant caPPR-induced cAMP-response element (CRE) activity levels by about 10-fold. Thus, in addition to the well known calcemic feedback system for PTH, local feedback regulation by the bone matrix protein OPN also plays a significant role in the regulation of PTH actions.

Protein-disulfide Isomerase-associated 3 (Pdia3) Mediates the Membrane Response to 1,25-Dihydroxyvitamin D3 in Osteoblasts

“…In wild-type MC3T3-E1 cells, three genes were up-regulated in response to1␣,25(OH) 2 D 3 : ALP is an early stage osteoblast differentiation marker (42); MMP-13 is an extracellular matrix remodeling proteinase (43); and OPN has been shown to be a mineralization inhibitor (44). Three genes were down-regulated.…”

Osteopontin regulates anabolic effect in human menopausal osteoporosis with intermittent parathyroid hormone treatment

“…OPN may play a pivotal role in net bone formation under intermittent PTH treatment in menopausal women. A previous report indicated that anabolic action was enhanced with an optimal dosage of PTH in mice deficient in OPN, suggesting that OPN plays a role as a local antagonist [32]. The mice had increased trabecular bone volume and a decrease in cortical bone thickness.…”

“…Because PTH regulates expression of OPN in osteoblasts, OPN could be one of the targets of PTH in the bone. A sequential decrease of OPN expression with concomitant bone formation may explain the mechanisms underlying PTH's anabolic action [32].…”

“…Animal studies have also shown that intermittent treatment with human PTH induces more bone formation in OPN-deficient mice and rescues ovariectomy-induced bone loss mice [31,32]. OPN inhibits mineral crystal growth in vivo and in vitro [33], but the regulatory mechanism of OPN in the treatment of human menopausal osteoporosis with intermittent PTH is still not clear.…”

The Usefulness of Mandibular and Maxillary Bone Derived from Neural Crest as Bone Graft Substitutes

“…Osteopontin promotes early differentiation of osteoblasts, their adhesion to bone, and subsequent bone formation. Furthermore, it enhances bone resorption by promoting the adhesion of osteoclasts to the bone surface 28,29 . To elucidate which bone graft materials might promote osteoblastic differentiation in the present experiments, we used immunohistochemistry for analysis of the distribution of osteopontin in mouse calvariae.…”